1. Field of the Invention
Angiotensin converting enzyme inhibitors (ACE inhibitors) are known to be useful for treatment of a variety of cardiovascular ailments such as hypertension, heart failure, myocardial infarction, left ventricular dysfunction and diabetic nephropathy. ACE inhibitors are believed to inhibit the action of angiotensin-converting enzyme (ACE) in the body in its conversion of angiotensin I, a relatively inactive peptide, to angiotensin II, a powerful vasoconstrictor and stimulant of the adrenal cortex for the secretion of aldosterone, which is normally associated with fluid retention. Angiotensin I is the product of the action of renin, which is produced by the kidneys, on angiotensinogen (a globulin of plasma). The action of an ACE inhibitor, by reducing conversion of angiotensin I, relieves vasoconstriction and reduces aldosterone secretion. It also provides negative feedback on renin release, which is also believed to decrease aldosterone secretion. ACE inhibitors also include angiotensin II antagonists.
Another possible basis for the effectiveness for ACE inhibitors is that ACE is identical to bradykininase (kininase II), which acts on bradykinin. Bradykinin stimulates prostaglandin biosynthesis and it is believed that ACE inhibitors also inhibit bradykininase and thereby increase bradykinin levels. ACE inhibitors thus stimulate the biosynthesis of prostaglandin, which is a vasodilator and which may contribute to the pharmaceutical effects of ACE inhibitors.
The physiological effects associated with ACE inhibitors include increases in serum potassium and sodium and fluid loss, a reduction of peripheral arterial resistance in hypertensive patients and an increase in cardio output with little or no change in heart rate. There is also an increase in renal blood flow, reduction in blood pressure and an improvement in maximal exercise tolerance in patients with heart failure.
ACE inhibitors are characterized as peptides that fall into three groups: sulfhydryl-containing (e.g., captopril), dicarbocyl-containing (e.g., enalapril, lisinopril, benazepril, quinapril, moexipril, trandolapril, and ramipril), and phosporous-containing (e.g., fosinopril). Other known ACE inhibitors are enalaprilat, irbesartan, losartan potassium, valsartan, zofenapril and ceranapril. The pharmaceutical dosages and administration of the various ACE inhibitors are known to those of ordinary skill in the art. Typically, the compositions are administered orally.
2. Related Art
In Drug Facts and Comparisons, January 2000, published by Facts and Comparisons, St. Louis, Mo., certain “adverse reactions” of various ACE inhibitors are shown, including reactions pertaining to the central nervous system. Some of these include confusion, depression, malaise, nervousness and anxiety. When the incidence of these reactions were given, they almost all were reported in less than one percent of the persons treated. In addition, the following reactions were reported at incidences of less than one percent of the persons treated: dream abnormality (in connection with enalapril); memory disturbance, mood change and behavior change (in connection with fosinopril); irritability (in connection with lisinopril) and mood changes (in connection with moexipril).
U.S. Pat. No. 5,049,553 entitled “Method For Preventing or Treating Symptoms Resulting From Closed Head Injuries Employing an ACE Inhibitor” issued on Sep. 17, 1991 to A. Sudilovsky. The '553 patent discloses the administration of an ACE inhibitor to treat symptoms brought on by head trauma which causes unconsciousness for twenty minutes or more. The stated symptoms include rages as well as memory loss, headache, dissociation of thought and depression, among others. See column 1, lines 60-64 and column 1, line 65 to column 2, line 17. The '553 patent also notes that ACE inhibitors are useful for treating hypertension; see the art cited at column 1, lines 27 to 59 and column 2, lines 18-20.